维奈克拉治疗白血病耐药的分子途径

Molecular pathways of leukemia resistance to treatment with venetoclax

维奈克拉(VEN)可以靶向B细胞淋巴瘤(BCL)-2蛋白,通过刺激线粒体凋亡通路诱导癌细胞凋亡,是目前白血病患者个性化治疗方案中的重要组成部分。随着近年来VEN应用范围的扩大,出现了一些VEN耐药的病例,给临床治疗带来了新的挑战。对VEN的耐药包括遗传和非遗传机制,如抗凋亡蛋白髓细胞白血病-1(MCL-1)与BCL-XL表达增加、BCL-2家族蛋白结构突变、BAX基因突变和缺失、其他癌基因如肿瘤蛋白P53(TP53)突变、FMS样酪氨酸激酶3(FLT3)内部串联重复序列(ITD)扩增、白血病干细胞(LSCs)线粒体代谢异常、线粒体形态和功能改变、肿瘤微环境影响、VEN代谢等。该文就VEN治疗白血病耐药机制进行综述和总结,并介绍了如何克服这些耐药机制的概念和策略。

Venetoclax is the first BH3 analog approved by the U.S.Food and Drug Administration to target the B cell lymphoma/leukemia(BCL)-2 protein and induce apoptosis in cancer cells by stimulating the mitochondrial apoptosis pathway.It has the potential to enhance cell death in a variety of leukemia treatment regimens and is currently an important component of personalized treatment regimens for leukemia patients.However,with the expansion of the application of venetoclax in recent years,some cases of resistance to venetoclax have emerged,posing a major problem for clinical treatment.Resistance to venetoclax includes both genetic and non-genetic mechanisms,which include increased expression of the anti-apoptotic proteins myeloid leukemia-1(MCL-1)and B-cell lymphoma-XL(BCL-XL),structural mutations in the BCL-2 family of proteins,mutations and deletions of the BCL-2-associated X-protein(BAX)gene,other oncogenes such as mutations in the gene tumor protein p53(TP53),amplification of internal tandem duplications(ITD)in FMS-like tyrosine kinase 3(FLT3),abnormal mitochondrial metabolism in leukemia stem cells(LSCs),alterations in mitochondrial morphology and function,effects of the tumor microenvironment,and venetoclax metabolism that cause the development of drug resistance.In addition,we present concepts and strategies on how to overcome these resistance mechanisms.A series of clinical trials in combination with venetoclax are currently underway,and therefore,understanding the mechanisms of resistance is critical to facilitate the development of new targeted therapeutic strategies as well as furthering our understanding of the biological function of BCL-2 in tumor cells.